WO 96/35685 discloses an (RRR)-optical isomer of 1,4-benzodioxin-2-carboxylic acid derivatives represented by the following general formula (7') which is useful as a prophylactic and therapeutic agent for diabetes, hyperglycemia and the like, and a process for the preparation thereof. ##STR2##
wherein R.sub.1 is hydroxy or (C.sub.1 -C.sub.4)alkoxy, and R.sub.2 and R.sub.3 may be the same or different, and each is hydrogen, halogen, (C.sub.1 -C.sub.6)alkyl, trifluoromethyl, (C.sub.1 -C.sub.6)alkoxy, aryl, aryloxy or aryl(C.sub.1 -C.sub.6)alkyloxy, the aryl, aryloxy or aryl(C.sub.1 -C.sub.6)alkyloxy being optionally substituted by one or two halogens, or R.sub.2 and R.sub.3 may together form --OCH.sub.2 O--. PA1 wherein R is as defined above. PA1 wherein R is as defined above, and R.sub.2 and R.sub.3 may be the same or different and each is hydrogen, halogen, (C.sub.1 -C.sub.6)alkyl, trifluoromethyl, (C.sub.1 -C.sub.6)alkoxy, aryl, aryloxy or aryl(C.sub.1 -C.sub.6)alkyloxy, the aryl, aryloxy or aryl(C.sub.1 -C.sub.6)alkyloxy being optionally substituted by one or two halogen atoms, or R.sub.2 and R.sub.3 together may form --OCH.sub.2 O--, can be prepared from the compound of formula (1) or (2) easily and in high yield. PA1 wherein R is as defined below and a compound of formula (4) ##STR7## PA1 wherein R is as defined below and X is (C.sub.1 -C.sub.4)acyl can be obtained by reacting a racemate of formula (3) ##STR8## PA1 wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with an acylating agent in the presence of a hydrolase. Separating the resultant mixture can provide each compound with high optical purity and in high yield. Further, the compound of formula (4) obtained above can be ##STR9## PA1 wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino. PA1 wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino. PA1 wherein R is as defined above and the compound of formula (2) ##STR12## PA1 wherein R is as defined above, which comprises the steps of: reacting the racemate of formula (3) ##STR13## PA1 wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with an acylating agent in the presence of a hydrolase to give the compound of formula (4) ##STR14## PA1 wherein R is as defined above and X is (C.sub.1 -C.sub.4)acyl and the compound of formula (2) ##STR15## PA1 wherein R is as defined above, followed by separation, and subjecting the compound of formula (4) to alcoholysis or hydrolysis. PA1 wherein R, R.sub.2 and R.sub.3 are as defined below, which comprises the steps of: PA1 wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino or the compound of formula (2) ##STR18## PA1 wherein R is (R)-1-phenylethylamino or (S)-1-phenyl-ethylamino with a halogenating agent or a sulfonylating agent, and condensing the resulting compound of formula (5) ##STR19## PA1 wherein R is as defined above and Y is halogen, (C.sub.1 -C.sub.4)alkylsulfonyloxy or arylsulfonyloxy with the compound of formula (6) ##STR20## PA1 wherein R.sub.2 and R.sub.3 may be the same or different, and each is hydrogen, halogen, (C.sub.1 -C.sub.6)alkyl, trifluoromethyl, (C.sub.1 -C.sub.6)alkoxy, aryl, aryloxy or aryl(C.sub.1 -C.sub.6)alkyloxy, the aryl, aryloxy or aryl(C.sub.1 -C.sub.6)alkyloxy being optionally substituted by one or two halogen atoms, or R.sub.2 and R.sub.3 together may form --OCH.sub.2 O--. PA1 (R represents (R)-1-phenylethylamino or (S)-1-phenylethylamino.)
According to a method disclosed in WO 96/35685, a compound of the above formula (7') is prepared as shown in the following Scheme I. A compound of formula (6) is reductively condensed with a compound of formula (8) to form a mixture of diastereoisomers of formula (9), which is then converted into an N-tert-butoxy carbonyl derivative of formula (10), and the derivative is separated into diastereoisomers of formulae (11) and (12) by column chromatography, and then a compound of formula (11) is hydrolyzed to prepare an (RRR)-optical isomer of 1,4-benzodioxin-2-carboxylic acid derivatives represented by the formula (7'). ##STR3##
The above-mentioned process has not been accepted as an efficient method, because it forms a compound of formula (12) which is not required for the production of a desired compound [formula (7')], which resulted in reducing a total yield of the desired compound.
Therefore, it has been demanded to efficiently produce an (RRR)-optical isomer of 1,4-benzodioxin-2-carboxylic acid derivatives represented by the formula (7'), which is useful as a prophylactic and therapeutic agent for diabetes, hyperglycemia and the like.